DNA methylation as a potential mediator of the association between indoor air pollution and neurodevelopmental delay in a South African birth cohort

Background and Aim Prenatal exposure to indoor air pollution (IAP) has been linked to neurodevelopmental delay in toddlers. Changes in DNA methylation (DNAm) have been independently associated with both prenatal air pollution exposure and delayed neurodevelopment. Investigating DNAm as a mediator may help to elucidate the biological pathways driving the association between IAP and neurodevelopmental delay. In this study, we aim to identify differentially methylated CpG sites and gene regions that mediate this association. Methods We analyzed data from 142 mother-child pairs enrolled in the South African Drakenstein Child Health Study. DNAm from cord blood was measured using the Infinium MethylationEPIC and HumanMethylation450 arrays. Particulate matter with an aerodynamic diameter of 10m or less (PM10) was measured inside participants’ homes during the second trimester of pregnancy. Neurodevelopment was assessed at age 2 years using the Bayley Scales of Infant and Toddler Development III in four domains (cognitive function, general adaptive behavior, language, and motor function). We used three high-dimensional mediation analysis techniques (HIMA, DACT and gHMA) to identify potential mediators, complemented with causal mediation analysis to assess the robustness of our results. Results Differential methylation at 29 CpG sites and 4 gene regions (GOPC, RP11-74K11.1, DYRK1A, RNMT) was found to significantly mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. Estimated proportion mediated (95%-confidence interval) ranged from 0.29 (0.01,0.86) for cg00694520 to 0.54 (0.11,1.56) for cg05023582. Conclusions DYRK1A and several of the genes our CpG sites mapped to, including CNKSR1, IPO13, IFNGR1, LONP2, and CDH1 are associated with biological pathways implicated in neurodevelopment and three of our identified CpG sites (cg23560546, cg22572779, cg15000966) have been previously associated with fetal brain development. These findings suggest that DNAm may mediate the association between prenatal PM10 exposure and cognitive neurodevelopment. Keywords: particulate matter, neurodevelopment, cord blood, epigenetics, newborn DNA methylation